Acrylate derivatives



United States Patent Office 3,365,448 ACRYLATE DERIVATIVES George Y. Lesher, Schodack, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 11, 1964, Ser. No. 388,940 6 Claims. (Cl. 260-240) This invention relates to acrylic acid derivatives.

The invention resides in the composition of matter having a molecular structure in which a lower-alkyl acrylate is substituted in the a-position of the acrylic acid moiety by 4-nitrobenzoyl and in the fJ-position by lower-alkylamino, phenylamino, pyridylamino, di (lower alkyl) amino, N-(lower-alkyl) N-phenylamino, N-(lower-alkyl) N-pyridylamino, piperidino, pyrrolidino, morpholino and piperazino.

Among the compounds of my invention are those of CHNB where R is lower-alkyl, NB is piperidino, (lower alkylated) piperidino, pyrrolidino, (lower-alkylated)-pyrrolidino, morpholino and (loweralkylated)-morpholino, R is lower-alkyl, phenyl or pyridyl, and R is hydrogen or lower-alkyl. Optionally, the aromatic rings of Formula I, i.e., 4-nitrophenyl of 4- nitrobenzoyl, and phenyl or pyridyl designated as R can be substituted by low-molecular weight substituents, e.g., halo, lower-alkyl, lower-alkylmercapto, lower-alkanoylamino, lower-alkylamino, amino, hydroxy, and the like, at any of the available ring positions and where more than one substituent is present, they can be the same or different and they can be in any of the various position combinations relative to each other. The halo substituents can be chloro, bromo, iodo or fluoro.

The term lower-alkyl, as used herein, e.g., as the meaning for R or as one of the meanings for R or R in Formula I, means alkyl radicals having from one to six carbon atoms and is illustrated by methyl, ethyl, npropyl, isopropyl, n-butyl, 2-butyl, isobutyl, n-amyl, isoamyl, n-hexyl, 3-hexyl, and the like. Similarly, other terms using the adjective lower, i.e., lower-alkylmercapto, lower-alkylamino and lower-alkanoylamino, means such radicals having from one to six carbon atoms.

The compounds of Formula I are prepared reacting a lower alkyl a-(ethoxymethylene) oc-(4 nitrobenzoyl) acetate (II) with an amine, HNB (III), as follows: Piperidino, pyrrolidino or morpholino when loweralkylated can have lower-alkyl substituents at any available ring position.

CHNB

I The reaction is illustrated in the specific examples below. The compounds of Formula I have been tested by standard in vitro bacteriological evaluation procedures 3,365,448 Patented Jan. 23, 1968 and found to possess antibacterial activity for example, against Staphylococcus aureus, Eberthella typhi, Clostridz'um welchii and Pseudomonas aeruginosa, at test concentration levels in the range of about 0.050 mg./cc. to about 1.0 mg./cc., as illustrated in the examples below.

The molecular structures of the compounds of my invention are established by their mode of synthesis and corroborated by the correspondence of calculated and found values for the elementary analyses and by infrared (IR) spectral and nuclear magnetic resonance (NMR) analyses.

The following examples will further illustrate the invention without, however, limiting it thereto.

EXAMPLE 1 The preparation of the intermediate lower-alkyl oc- (ethoxymethylene) a (4-nitrobenzoyl)acetate is illustrated as follows for the ethyl ester: A mixture containing 98 g. of ethyl 4-nitrobenzoylacetate, g. of triethyl orthoformate and 145 g. of acetic anhydride was heated with stirring on a steam bath for forty-eight hours. The reaction mixture was then evaporated by heating in vacuo using the bath temperature of C. to yield, as an oily residue, the crude intermediate, ethyl m-(ethoxymethylene)-a-(4-nitrobenzoyl)acetate, which was used without further purification in the following examples to prepare the final products.

The corresponding methyl, isopropyl, n-butyl or nhexyl a-(ethoxymethylenc-a- 4-nitrobenzoyl) acetate is obtained by following the above procedure using molar equivalent quantities of methyl, isopropyl, n-butyl 01' nhexyl 4-nitrobenzoylacetate in place of ethyl-4-nitrobenzoylacetate.

EXAMPLE 2 Ethyl B-a'iethylamino a (4-m'rrob enzoyl) acetate-To 14.6 g. of ethyl a-(ethoxymethylene)-a-'(4-nitrobenzoyl) acetate was added slowly with cooling and stirring 10 ml. of diethylamine. The reaction mixture was stirred at room temperature for one hour and then allowed to stand at room temperature overnight. The excess diethylamine was removed by heating the mixture on a steam bath in vacuo and the residual material was taken up in ethylene dichloride. The resulting solution was washed successively with 2 N hydrochloric acid, 5% aqueous potassium bicarbonate solution and water; dried over anhydrous potassium carbonate; treated with decolorizing charcoal and filtered; and then evaporated. The oily residue was triturated with cyclohexane with cooling whereupon solidification resulted. The solid was recrystallized twice using EXAMPLE 3 Ethyl fl-ethylamino-a- (4-nitr0benz0yl) acrylate.To a solution containing 14.6 g. of ethyl u-(ethoxymethylene)- a-(4-nitrobenzoyl)acetate in 50 ml. of ethanol was added 15 ml. of ethylamine in 100 ml. of ethanol with stirring at room temperature. The reaction mixture was allowed to stand at room temperature for thirty minutes; the precipitated product was collected and recrystallized from isopropyl alcohol to yield 8.0 g. of ethyl fi-ethylaminoa-(4-nitrobenzoyl) acrylate, M.P. 137.2-138.0 C. (corn).

Analysis.Calcd. for c14H1 N205: C, H, N, 9.59. Found: C, 57.86; H, 5.72; N, 9.80.

Ethyl fl-ethylamino-u (4 nitrobenzoyl)acrylate was found to have bacteriostatic activity against Pseudomonas aeruginasa at a concentration of 0.10 mg./ cc.

EXAMPLE 4 Ethyl fl-methylamino-w(4-nitrobenz0yl)acrylate. A mixture containing 14.6 g. of ethyl a-(ethoxymethylene)- a-(4-nitrobenzoyl)acetate and 50 ml. of 40% methylamine in water was stirred for one hour. The resulting precipitate was collected and recrystallized from isopropyl alcohol using decolorizing charcoal to yield 11 g. of ethyl fi-methylamino-a-(4-nitrobenzoyl)acrylate, M.P. 153.6- 154.8 C. (corn).

Analysis.-Calcd. for C13H14N205Z C, 56-11; H, N, 10.07. Found: C, 56.27; H, 5.28; N, 10.02.

Ethyl p-methylamino-m-(4-nitrobenzoyl)acrylate was found to have both bacteriostatic and bactericidal activities against Clostridium welchii at a concentartion of 0.10 mg./ cc.

EXAMPLE Ethyl 13 (4 bromoanilino) a (4 nitrobenzoyl) acrylate.-A solution containing 1.7 g. of 4-bromoanilino in ml. of ethanol was added to a solution of 2.9 g. of ethyl ot-(ethoxymethylene)-a-(4-nitrobenzoyl) acetate in 10 ml. of ethanol at room temperature and the reaction mixture was stirred for one hour. The resulting precipitate was collected and recrystallized from isopropyl alcohol to yield 4.5 g. of ethyl fi-(4-bromoanilino)-a-(4-nitrobenzoyl)acrylate, M.P. 155.0156.8 C. (corn).

Analysis.-Calcd. for C H BrN O Br, 19.06; N, 6.68. Found: Br, 19.28;N, 6.65.

The structure of the above compound was confirmed by nuclear magnetic resonance analysis.

Ethyl fl- (4-bromoanilino -u- (4-nitrobenzoyl) acrylate was found to have bacteriostatic activity against Staphylococcus aureus, Eberthella typhi, Clostridium welchii and Pseudomonas aeruginosa at respective concentrations of 0.10, 0.10, 0.10 and 0.075 rag/cc.

EXAMPLE 6 Ethyl ,6-(G-methyZ-Z-pyridylamina)-u-(4-nitr0benz0yl) acrylate.To a solution containing 14.6 g. of ethyl 0t- (ethoxymethylene)-a-(4-nitr0benzoyl)acetate in 40 ml. of ethanol was added 5.4 g. of 2-amino-6-methylpyridiue in 30 ml. of ethanol and the resulting mixture was stirred for one hour. The precipitate was collected and recrystallized from isopropyl alcohol using decolorizing charcoal to yield 13 g. of ethyl fi-(6-methyl-2-pyridylamino)-u-(4- nitrobenzoyl)acrylate, M.P. 176.2177.0 C. (corn).

Analysis.Calcd. for C H N O C, 60.81; H, 4.82; N, 11.83. Found: C, 61.10; H, 5.06; N, 11.75.

Ethyl 13- G-methyl-Z-pyridylamino -a- (4-nitrobenzoyl) acrylate was found to have bacteriostatic and bactericidal activities against Staphylococcus aureus at respective concentrations of 0.05 and 0.10 mg./cc., and to have bacteriostatic activity against Eberthella typhi, Clostridium welchii and Pseudomonas aeruginosa at respective concentrations of 0.10, 0.075 and 0.10 mg./cc.

EXAMPLE 7 Methyl S-dimethylamina-a-(4-nitr0benzoyl)acrylate is prepared following the procedure described in Example 2 using molar equivalent quantities of methyl a-(ethoxymethylene)-a-(4-nitrobenzoyl) acetate and dimethylamine.

EXAMPLE 8 Isopropyl fl-di-n-butylamino-a-(4-nitrobenzoyl) acrylate is prepared following the procedure described in Example 2 using molar equivalent quantities of isopropyl oc- (ethoxymethyleneya-(4-nitrobenzoyl)acetate and di-nbutylamine.

4 EXAMPLE 9 n-Butyl p-n-hexylamino-u-(4-nitr0benz0yl)acrylate is prepared following the procedure described in Example 3 using molar equivalent quantities of n-butyl a-(ethoxymethylene)-a-(4-nitrobenzoyl)acetate and n-hexylamine.

EXAMPLE 10 n-Hexyl ,8-(N-methylanilino)-a-(4-nitr0benz0yl)acrylate is prepared following the procedure described in Example 5 using molar equivalent quantities of n-hexyl a- (ethoxymethylene) a (4-nitrobenzoyl)acetate and N- methylaniline.

EXAMPLE 11 Ethyl ot-(4-nitr0benz0yl)-;8-(4-pyridylamino)acrylate is prepared following the procedure described in Example 6 using molar equivalent quantities of ethyl a-(ethoxymethylene)-u-(4-nitrobenzoyl)acetate and 4-arninopyridine.

EXAMPLE 12 Ethyl ot-(4-nitr0benz0yl) -;8-(3-pyridylamino)acrylate is prepared following the procedure described in Example 6 using molar equivalent quantities of ethyl a-(ethoxymethylene) or. (4-nitrobenzoyl)acetate and 3-amin0pyridine.

EXAMPLE 13 Ethyl 3-(N-methyl-Lpyridylamino)-a-(4-nitr0benz0yl) acrylate is prepared following the procedure described in Example 6 using molar equivalent quantities of ethyl a- (ethoxymethylene) -a-(4-nitr0benzoyl)acetate and Z-methylaminopyridine.

EXAMPLE 14 Ethyl a-(4-nitrobenzoyl)-B-piperidin0acrylate is prepared following the procedure described in Example 2 using molar equivalent quantities of ethyl a-(ethoxymethylene)-a-(4-nitrobenzoyl)acetate and piperidine.

EXAMPLE 15 Ethyl fl-(3-ethylpiperidino)-a-(4-nitr0benz0yl)acrylate is prepared following the procedure described in Example 2 using molar equivalent quantities of ethyl a-ethoxymethylene)-a-(4-nitrobenzoyl)acetate and 3-ethylpiperidine.

EXAMPLE 16 Ethyl fl-(2,6-dimethylpiperidin0)-a-(4-nitr0benz0yl)acrylate is prepared following the procedure described in Example 2 using molar equivalent quantities of ethyl a-(ethoxymethylene)-a-(4nitrobenzoyl)acetate and 2,6- dimethylpiperidine.

EXAMPLE 17 Ethyl a-(4-nitr0benz0yl)-fi-pyrrolidinoacrylate is prepared following the procedure described in Example 2 using molar equivalent quantities of ethyl a-(ethoXymethylene)-a-(4-nitrobenzoyl)acetate and pyrrolidine.

EXAMPLE l8 Ethyl fi-(Z-methylpyrrolidino)-ot-(4-nitr0benz0yl)actylate is prepared following the procedure described in Example 2 using molar equivalent quantities of ethyl a-(ethoxymethylene) a (4-nitrobenzoyl)acetate and 2- methylpyrrolidin.

EXAMPLE 19 Ethyl fl-morpholino-m-(4-nitr0benz0yl)acrylate is prepared following the procedure described in Example 2 using molar equivalent quantities of ethyl a-(ethoxymethylene) -u-(4-nitrobenzoyl) acetate and morpholine.

I claim:

1. A compound of the formula CHNB 5 6 Where R is lower-alkyl, NB is a member of the group 2. Ethyl B-diethylamino-a-(4-nitrobenzoy1)acrylate. consisting of 3. Ethyl B-ethylamino-u-(4-nitrobenzoyl)acrylate.

R1 4. Ethyl fl-methylamino-a-(4-nitrobenzoyl)acrylate. 5. Ethyl 13 (4-bromoan'ilino)-a-(4-nitr0benz0yl)acry- 5 late.

R2 6. Ethyl 13 (6 methyl 2 pyridylamino) a (4- piperidino, (lower-alkylated)-piperidino, pyrrolidino, mtrobenzoynacrylate- (lower-alkylated)-pyrrolidino, morpholino and (loweralky1ated)-morpholino, R is a member selected from the References Cited group consisting of lower-alkyl, phenyl and pyridyl, R is 10 Panizzi, Gazz. Chim. ItaL, vol. 73, pp. 13 to 19 (1943).

a member selected from the group consisting of hydrogen and lower-alkyl, JOHN D. RANDOLPH, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,365,448 January 23, 1968 George Y. Lesher It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 29, "q- (eth0xymethylene-a-" should read oz- (ethoxymethylene) aline 35 "acetate" should read acrylate Signed and sealed this 13th day of January 1970.

(SEAL) Attest:

Edward M. Fletcher, J r.

Attesting Officer Commissioner of Patents WILLIAM E. SCHUYLER, JR. 

1. A COMPOUND OF THE FORMULA
 6. ETHYL B - (6 - METHYL - 2 PYRIDYLAMINO) - A - (4NITROBENZOYL)ACRYLATE. 